Acute ischemic renal failure is associated with high morbidity and mortality. In renal transplantation ischemia/reperfusion injury is associated with delayed graft function and decreased long-term graft survival. The long-term objective of this program is to use long-acting selective A2A-agonists in reducing renal injury from ischemia/reperfusion in humans. As a step toward this goal, the current proposal describes methods in a rodent model of ischemia/reperfusion injury to develop and test novel long-acting selective A2A-adenosine receptor agonists as compounds to reduce renal tissue injury. Aim l describes experiments to identify and characterize novel selective long- acting A2A-agonists. We plan to identify the metabolites that accumulate in animals. Specificity will be assessed by radioligand binding and functional assays in human inflammatory cells. Aim 2 describes experiments to determine the specificity of action of A2A- agonists in vivo and the window of time during which a A2A agonist must be administered in order to produce optimal tissue protection. We will use a well established mouse model of I/R injury. These compounds will be commercialized by a new Biotechnology start-up company, Adenosine Therapeutics, LLC. PROPOSED COMMERCIAL APPLICATIONS: We propose to synthesize, characterize and commercialize novel adenosine A2A agonists in order to reduce injury in renal ischemia1reperfusion. Acute renal failure is a common disorder affecting 5% of hospitalized patients and is associated with a mortality of approximately 50%. Based upon our preliminary data, new compounds that we develop for this use, long- acting selective agonists of A2A adenosine receptors, should be potent agents in reducing renal injury.